Greater lesion damage is bidirectionally related with accelerated brain aging after stroke.

Regional neuron loss following stroke can result in remote brain changes due to diaschisis and secondary brain atrophy. Whole brain changes post-stroke can be captured by the predicted brain age difference (brain-PAD), a neuroimaging-derived biomarker of global brain health previously associated with poorer chronic stroke outcomes. We hypothesized that greater lesion damage would be longitudinally associated with worsening brain-PAD during subacute stroke, and conversely, that poorer baseline brain-PAD would be associated with enlarged lesion damage. We prospectively collected MRIs from 47 stroke patients across three sites within 3 weeks (baseline) and at 3 months (follow-up) post-stroke. Predicted brain age was estimated via a pretrained ridge regression model using 77 morphological features. Brain-PAD was calculated as predicted age minus chronological age. Robust linear mixed effects regression models were used to examine relationships between infarct volume and brain-PAD, adjusting for age, sex, time, and intracranial volume at baseline. Larger baseline infarct volume was associated with accelerated brain aging at 3 months (β=0.87, p=0.023). Conversely, larger baseline brain-PAD predicted larger increase in infarct volume at 3 months (β=0.02, p=0.009). These findings reveal a bidirectional relationship between focal stroke damage and global brain health during the subacute period, underscoring the importance of assessing both.